{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe urokinase‐type plasminogen activator (PLAU, also known as uPA) is a key serine protease that, upon binding to its high‐affinity receptor uPAR, initiates a proteolytic cascade converting plasminogen into plasmin. This reaction leads to extracellular matrix degradation, which in turn facilitates cell adhesion, migration, invasion, and metastasis observed in a range of human cancers. Its central role in remodeling the tumor microenvironment is underscored by structural studies and clinical correlations in diverse malignancies such as breast, prostate, lung, and gastric cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPLAU’s expression, activation, and turnover are tightly regulated at multiple levels. Posttranscriptionally, RNA‐binding proteins such as HuR and kinases like MK2 modulate uPA mRNA stability, while epigenetic mechanisms—including promoter hypermethylation in early prostate cancer—silence its expression. At the posttranslational level, specific microRNAs (for example, miR‑193a and miR‑23b) have been shown to directly target PLAU transcripts, thereby reducing uPA protein levels and consequent cell invasion. In addition, activation of the latent pro‐enzyme requires proteolytic cleavage by transmembrane serine proteases including matriptase and hepsin, and its activity may be negatively regulated by endogenous inhibitors such as maspin and even by tumor‐suppressing functions of CFTR."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its proteolytic function, PLAU mediates a variety of cell signaling events. Its binding to uPAR triggers intracellular cascades through cooperation with other cell surface receptors—including integrins and the epidermal growth factor receptor (EGFR)—thereby activating pathways such as ERK/MAPK, PI3K/Akt, and NF‑κB. These signaling events contribute not only to enhanced motility, proliferation, and epithelial–mesenchymal transition (EMT) of cancer cells, but also to resistance to apoptosis. Moreover, uPA‐dependent signaling facilitates nuclear translocation and transcriptional regulation, further promoting an aggressive and invasive tumor phenotype."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond tumor cells, the PLAU system additionally contributes to processes in normal and inflammatory settings. In immune cells such as neutrophils and basophils, uPA binding to uPAR cooperates with integrins to regulate adhesion, migration, and fibrinolysis, which are essential for tissue repair and inflammation. These multifaceted roles of PLAU, along with its correlation with advanced tumor grade and poor clinical outcome, underscore its potential both as a prognostic biomarker and as a therapeutic target in oncology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Takeshi Kaneko, Hiroyuki Konno, Megumi Baba, et al. 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